Abstract
Peroxisome proliferator-activated receptor gamma (PPARγ) is a ligand-activated nuclear receptor that regulates glucose and lipid metabolism. Pharmacological activators of PPARγ are being used as a treatment of obesity related disorders such as dyslipidaemia and type 2 diabetes, but questions remain open regarding the effects of PPARγ on traits related to the development of type 2 diabetes. In our study, we have analyzed the relationship of the common variant Pro12Ala in the human PPARγ2 gene with the presence of obesity and with insulin, HOMA and lipid profile in a representative sample of 6-to 8-year-old children free from the confounding factors associated with adults. We found that Ala12Ala genotype was significantly more frequent in females with obesity than in those without obesity, with Ala12Ala carriers having significantly higher weight and body mass index (BMI), however the association disappeared when adjusting by leptin concentrations. The Ala12Ala genotype was associated with significantly higher HDL-cholesterol and apoA-I levels in males but not in females, independently of BMI. In a recessive model, in females, leptin levels appeared higher in Ala12Ala carriers. Although no apparent differences were observed in any sex when analyzing insulin levels and HOMA among genotypes without adjusting, lower insulin levels and lower HOMA appeared associated with Ala12Ala carriers when adjusting for BMI and leptin levels. In summary, our data showed that leptin seems to be having an effect on the association between the PPARγ2 Pro12Ala and BMI. Besides, after controlling for BMI and leptin, a protective effect of the Ala12Ala variant of the PPARγ2 Pro12Ala polymorphism on insulin sensitivity is evident already in prepubertal children.
Highlights
The dysregulation of the homeostatic processes associated with obesity results in metabolic disorders originating atherosclerosis and type 2 diabetes
The genotype distribution of the Pro12Ala PPARγ2 polymorphism in our cohort was as follows: 84.4% (n 1,058) homozygote carriers of the wild-type genotype coding for proline (Pro12Pro); 14.9% (n 187) heterozygote carriers (Pro12Ala) and 0.7% (n 9) homozygote carriers of the alanine coding genotype (Ala12Ala)
The relationship of the PPARγ2 polymorphisms with obesity, insulin sensitivity and lipid profile has been extensively investigated, mainly in adults, with inconsistent results (Deeb et al, 1998; Mori et al, 1998; Mancini et al, 1999; Ringel et al, 1999; Altshuler et al, 2000; Hara et al, 2000; Oh et al, 2000; Douglas et al, 2001; Ek et al, 2001; Masud et al, 2003; Rosmond et al, 2003; Radha et al, 2006; Tönjes et al, 2006; Florez et al, 2007). In this cross-sectional study, the association of Pro12Ala PPARγ2 polymorphism with obesity, plasma lipids, insulin and leptin concentrations, as well as insulin resistance estimated using the homeostasis model assessment for insulin resistance (HOMA) (Matthews et al, 1985) is investigated in a population-based sample of children in whom the effect of several factors such as sex hormones, alcohol consumption, smoking etc. that may contribute to the discrepancies observed in adults can be avoided
Summary
The dysregulation of the homeostatic processes associated with obesity results in metabolic disorders originating atherosclerosis and type 2 diabetes. Among the PPAR family, PPARγ plays a central role in glucose homeostasis and adipocyte differentiation and has been related with diabetes mellitus (Kwak et al, 2002). In this sense, PPARγ ligands of the antidiabetic thiazolidinediones group are being used as a treatment of obesity comorbidities such as dyslipidaemia and type 2 diabetes (Cariou et al, 2012), but questions have arisen in this regard (Gross et al, 2017) as the development of these pharmacological activators of PPARγ requires a complete knowledge of the PPARγ-regulated control of glucose and lipid metabolism (Cataldi et al, 2021). A deeper knowledge of PPARγ physiological role will contribute to better understand the functionality of these PPARγ agonists on preventing type 2 diabetes
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